1. Field of the Invention
The present invention relates generally to the fields of biochemistry and pharmacology. More specifically, the present invention relates to a treatment of neurologic diseases such as amyotrophic lateral sclerosis using compounds such as metalloporphyrins or derivatives thereof.
2. Description of the Related Art
The low molecular weight metalloporphyrins (MPs) comprise a general class of compounds that contain a tetra-coordinated metal atom and various cationic, anionic, or uncharged functional groups extending outward from the planar porphyrin ring (FIG. 1). Many compounds in this class possess four identical functional groups making the molecule symmetrical. The nature of the functional groups can dramatically alter the redox behavior of the transition metal-containing porphyrins (1).
The manganese-containing porphyrins are perhaps the most extensively studied, largely because of the ability of some Mn-porphyrins to undergo cyclic one-electron oxidation and reduction under physiological conditions and thereby mimic some of the enzymatic properties of superoxide dismutases (2-5). Other catalytic activities of the Mn-porphyrins have been described, including the ability to decompose hydrogen peroxide (6) and peroxynitrite (7-9). Mammalian cells eliminate hydrogen peroxide primarily via the actions of catalase and glutathione peroxidase and scavenge superoxide with two copper, zinc-containing superoxide dismutases and one manganese-containing form. Glutathione peroxidase, in the presence of glutathione, has been shown to b e capable of catalytically decomposing peroxynitrite (10), raising the possibility that glutathione peroxidase or other selenoproteins may serve as natural peroxynitrite scavengers. However, protein tyrosine nitration occurs even under physiological conditions (and increases dramatically in pathologic states) indicating that at least some peroxynitrite escapes whatever endogenous detoxification systems may exist (11). Thus, compounds with the potential to catalytically decompose or otherwise scavenge peroxynitrite hold great promise as therapeutic agents in a number of disease conditions (11).
The ability of transition metal-containing metalloporphyrins to protect against peroxynitrite-mediated injury in vivo depends primarily on three properties: 1) how fast the metalloporphyrins react with peroxynitrite anion, i.e., how well they channel it into a metalloporphyrin-mediated reaction pathway, 2) how fast, and under what conditions the metalloporphyrins recycle to the reduced starting compounds, and 3) how well the metalloporphyrins contain or quench the resulting reactive intermediates. The rate constants for simple bimolecular reactions of some Mn- (8,12,13) and Fe-porphyrins (7) with peroxynitrite exceed 106 Mxe2x88x921sxe2x88x921, suggesting that they can potentially compete with many biomolecular targets which are known to react more slowly. Manganese porphyrins are capable of catalytically decomposing peroxynitrite in the presence of reductants like ascorbate or Trolox (8,12,13). At least one iron-porphyrin, iron(III)-meso-tetra-(N-methyl-4-pyridyl)-porphine chloride (FeTMPyP) has been shown to catalytically decompose peroxynitrite in the absence of added reductants, suggesting that re-reduction of the intermediate Fe(IV) form was not rate-limiting (7); this is explained, in part, by the recent work of Lee et al. (14) which indicates that peroxynitrite can also be decomposed by the intermediate Fe(IV) form of FeTMPyP. However, the ability of either Mn- or Fe-porphyrins to contain or quench reactive intermediates has not been rigorously examined and the precise mechanisms by which Mn and Fe porphyrins protect against oxidant-mediated injury in vivo have not been established.
The prior art is deficient in the lack of effective iron(III) porphyrins and their derivatives and analogs as a means of treating neurologic diseases such as amyotrophic lateral sclerosis (ALS). The present invention fulfills this longstanding need and desire in the art.
The present invention shows that there is abundant evidence for oxidant-mediated injury to motor neurons in ALS and a strong rationale for use of novel antioxidant compounds like the metalloporphyrins. In one embodiment of the present invention, there is provided a compound of the formula 
where R is selected from the group consisting of PhCO2CH3, Ph(3,5-OH)2, PhCH2OH, PhOCH3, PhPO3xe2x88x922, Ph(3-NO2-4-OH), PhNO2xe2x88x92, PhOPO3xe2x88x922, PhOSO3xe2x88x922, PhCH2CO2xe2x88x92, PhNH2, and PhCONH2. In another embodiment of the present invention, there is provided a pharmaceutical composition, comprising these compounds and additional compounds where R also may be PhCO2xe2x88x92 and PhSO3xe2x88x92 and a pharmaceutically acceptable carrier.
In another embodiment of the present invention, there is provided a method of treating an individual with Amyotrophic Lateral Sclerosis in need of such treatment comprising the step of administering to the individual a pharmacologically effective dose of the instant pharmaceutical compositions.
In yet another embodiment of the present invention, there is provided a method of treating an individual with neurodegenerative disease involving motor neuron death in an individual in need of such treatment comprising the step of administering to the individual a pharmacologically effective dose of the instant pharmaceutical compositions or pharmacologically acceptable salts thereof.
In yet another embodiment of the present invention, there is provided a preservation solution for donor organs, the solution comprising the compounds of the present invention or a pharmacologically acceptable salt thereof.
Other and further aspects, features, and advantages of the present invention will be apparent from the following description of the presently preferred embodiments of the invention given for the purpose of disclosure.